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Vol. 30, Issue 9, 962-969, September 2002
Division of Drug Delivery and Disposition, School of Pharmacy,
University of North Carolina, Chapel Hill, North Carolina (H.X.,
G.M.P., K.L.R.B.); Graduate School of Pharmaceutical Sciences,
University of Tokyo, Tokyo, Japan (H.S., Y.S.); and Division of
Clinical Pharmacology and Toxicology, Department of Medicine,
University Hospital Zurich, Zurich, Switzerland (P.J.M.)
Previous studies have demonstrated that phenobarbital (PB)
significantly impairs the biliary excretion of acetaminophen
glucuronide (AG) in rats. Studies also suggested that Mrp2 mediates AG
biliary excretion, and Mrp3 is involved in AG basolateral export. It
was hypothesized that inhibition of Mrp2-mediated AG transport by PB or
PB metabolites, and PB induction of Mrp3, may contribute to the
impaired biliary excretion of AG by PB. In the present study, the
hepatobiliary transport of AG in single-pass isolated perfused Wistar
and TR
rat livers was investigated. The AG biliary
clearance was markedly decreased, and the AG basolateral clearance was
significantly increased in TR rat livers. Uptake of AG by
Mrp2 and Mrp3, and inhibition of Mrp2- and Mrp3-mediated transport by
PB and major PB metabolites, were investigated with rat Mrp2- or
Mrp3-expressing Sf9 cell plasma membrane vesicles (Sf9-PMVs). AG was
transported by Mrp3 (Km 
0.91 mM).
Net ATP-dependent AG uptake into Mrp2-expressing Sf9-PMVs could not be
detected directly. However, AG significantly inhibited Mrp2-mediated
5-(and 6)-carboxy-2',7'-dichlorofluorescein (CDF) transport.
p-Hydroxyphenobarbital glucuronide
(p-OHPBG), but not PB or
p-hydroxyphenobarbital, significantly inhibited
Mrp2-mediated CDF transport. The IC50 values for
p-OHPBG inhibition of Mrp2-mediated CDF uptake and
Mrp3-mediated AG transport were similar (~0.68 and 0.46 mM,
respectively). PB treatment (80 mg/kg/day × 4 days) markedly
increased hepatic Mrp3 expression in Wistar rats. In conclusion,
inhibition of Mrp2-mediated AG transport by p-OHPBG provided one possible explanation for the impaired biliary excretion of
AG after acute PB treatment. However, impaired biliary excretion of AG
after PB pretreatment may be attributed primarily to the induction of
hepatic Mrp3 by PB.
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